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Abstract

Disease tolerance is the ability of the host to reduce the effect of infection on host fitness. Analysis of disease tolerance pathways could provide new approaches for treating infections and other inflammatory diseases. Typically, an initial exposure to bacterial lipopolysaccharide (LPS) induces a state of refractoriness to further LPS challenge (endotoxin tolerance). We found that a first exposure of mice to LPS activated the ligand-operated transcription factor aryl hydrocarbon receptor (AhR) and the hepatic enzyme tryptophan 2,3-dioxygenase, which provided an activating ligand to the former, to downregulate early inflammatory gene expression. However, on LPS rechallenge, AhR engaged in long-term regulation of systemic inflammation only in the presence of indoleamine 2,3-dioxygenase 1 (IDO1). AhR-complex-associated Src kinase activity promoted IDO1 phosphorylation and signalling ability. The resulting endotoxin-tolerant state was found to protect mice against immunopathology in Gram-negative and Gram-positive infections, pointing to a role for AhR in contributing to host fitness.

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Change history

  • 09 July 2014

    Affiliation address 9, for author David Gilot, was given incorrectly and has been updated.

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Acknowledgements

This work was supported by funding from the Italian Association for Cancer Research (AIRC, to P.P.), Fondazione Italiana Sclerosi Multipla Project No. 2010/R/17 (to F.F.), Associazione Umbra Contro il Cancro (to G.S. & M.A.D.F.), Bayer Grants4Target Focus Grant no. 2012-03-0630 (to A.I., F.F. and D.M.), Bayer Early Career Investigator Award (to D.M.), Grant no. R01ES007685 from the US National Institutes of Environmental Health Sciences (to M.S.D.), the Specific Targeted Research Project FUNMETA (to L.R.), and the Italian Ministry of Health in association with Regione dell’Umbria (GR-2008-1138004 to C.O.) We thank D. Fuchs for serum kynurenine determinations. We also thank G. Andrielli for digital art and image editing and G. Ricci for histopathology.

Author information

Author notes

    • Alban Bessede
    •  & Marco Gargaro

    These authors contributed equally to this work.

Affiliations

  1. Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy

    • Alban Bessede
    • , Marco Gargaro
    • , Maria T. Pallotta
    • , Davide Matino
    • , Giuseppe Servillo
    • , Cinzia Brunacci
    • , Carmine Vacca
    • , Rossana Iannitti
    • , Luciana Tissi
    • , Claudia Volpi
    • , Maria L. Belladonna
    • , Ciriana Orabona
    • , Roberta Bianchi
    • , Maria A. Della Fazia
    • , Danilo Piobbico
    • , Teresa Zelante
    • , Luigina Romani
    • , Ursula Grohmann
    • , Francesca Fallarino
    •  & Paolo Puccetti
  2. IMS Laboratory, University of Bordeaux, 33607 Pessac, France

    • Alban Bessede
    • , Michel Geffard
    •  & Bernard Veyret
  3. Center for Genome Research, University of Modena and Reggio Emilia, 41125 Modena, Italy

    • Silvio Bicciato
    •  & Emilia M. C. Mazza
  4. Department of Chemistry and Technology of Drugs, University of Perugia, 06123 Perugia, Italy

    • Antonio Macchiarulo
  5. Experimental Neuroimmunology Unit, German Cancer Research Center, 69120 Heidelberg, Germany

    • Tobias V. Lanz
    •  & Michael Platten
  6. Department of Neurooncology, University Hospital, 69120 Heidelberg, Germany

    • Tobias V. Lanz
    •  & Michael Platten
  7. Center for Advanced Research and Education, Asahikawa Medical University, 078-8510 Asahikawa, Japan

    • Hiroshi Funakoshi
  8. Kringle Pharma Joint Research Division for Regenerative Drug Discovery, Center for Advanced Science and Innovation, Osaka University, 565-0871 Osaka, Japan

    • Toshikazu Nakamura
  9. CNRS UMR6290, Institut de Génétique et Développement de Rennes, Université de Rennes 1, 35043 Rennes, France

    • David Gilot
  10. Department of Environmental Toxicology, University of California, Davis, 95616 California, USA

    • Michael S. Denison
  11. Australian School of Advanced Medicine (ASAM), Macquarie University, 2109 New South Wales, Australia

    • Gilles J. Guillemin
  12. Lankenau Institute for Medical Research, Wynnewood, 19096 Pennsylvania, USA

    • James B. DuHadaway
    •  & George C. Prendergast
  13. New Link Genetics Corporation, Ames, 50010 Iowa, USA

    • Richard Metz
  14. Bioceros, 3584 Utrecht, The Netherlands

    • Louis Boon
  15. Department of Medicine, University of Perugia, 06132 Perugia, Italy

    • Matteo Pirro
  16. Department of Clinical Epidemiology & Biostatistics, McMaster University, Ontario L8S 4K1, Canada

    • Alfonso Iorio

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Contributions

A.B. and M.G. designed and conducted all experiments unless otherwise indicated below; M.T.P., D.M. and C.V. analysed IDO and Src phosphorylation; S.B., E.M.C.M., D.P., M.P. and A.I. conducted bioinformatics studies and statistical analysis. A.M. performed homology modelling and docking studies. R.I., T.Z., M.A.D.F., L.R. and L.T. conducted the in vivo studies with Salmonella and GBS. C.V., M.L.B., C.O., G.S., C.B. and R.B. contributed to specific experimental designs; T.V.L., M.P., H.F. and T.N. made possible, and designed, the experiments with TDO2-deficient mice; J.B.D., G.C.P. and R.M. made possible, and designed, the experiments with IDO2-deficient mice; D.G., M.S.D., G.J.G., M.G., B.V., L.B. and U.G. provided conceptual help and reagents throughout experimentation; F.F. designed and supervised all experiments; P.P. supervised the overall study and wrote the manuscript. F.F. and P.P. share senior authorship on this paper.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Francesca Fallarino or Paolo Puccetti.

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DOI

https://doi.org/10.1038/nature13323

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